An Integrated Index: Engrams, Place

Cells, and Hippocampal Memory Travis

D. Goode & Kazumasa Z. Tanaka &
Amar Sahay & Thomas J. Mchugh
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 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011

ll

Perspective
An Integrated Index: Engrams,
Place Cells, and Hippocampal Memory
Travis D. Goode,1,2,3,4,7 Kazumasa Z. Tanaka,5,7 Amar Sahay,1,2,3,4,* and Thomas J. McHugh6,*
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Harvard Stem Cell Institute, Cambridge, MA 02138, USA
3Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
4Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
5Memory Research Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, Kunigami-gun, Okinawa, Japan
6Laboratory for Circuit and Behavioral Physiology, RIKEN Center for Brain Science, Wakoshi, Saitama, Japan
7These authors contributed equally

*Correspondence: asahay@mgh.harvard.edu (A.S.), thomas.mchugh@riken.jp (T.J.M.)

https://doi.org/10.1016/j.neuron.2020.07.011

SUMMARY

The hippocampus and its extended network contribute to encoding and recall of episodic experiences.
Drawing from recent anatomical, physiological, and behavioral studies, we propose that hippocampal en-
grams function as indices to mediate memory recall. We broaden this idea to discuss potential relationships
between engrams and hippocampal place cells, as well as the molecular, cellular, physiological, and circuit
determinants of engrams that permit flexible routing of information to intra- and extrahippocampal circuits for
reinstatement, a feature critical to memory indexing. Incorporating indexing into frameworks of memory func-
tion opens new avenues of study and even therapies for hippocampal dysfunction.

Introduction Space and Memory

A few keywords typed into the Google search bar will, more often
than not, immediately lead to the exact piece of information we
are seeking. While the details of how this magic happens are pro-
prietary, the general idea is transparent; Google has managed to
index vast swaths of the internet and uses our search terms to
quickly point to the most appropriate information (https://www.
google.com/search/howsearchworks). The system is surpris-
ingly flexible, using history, context, or location to hone results;
completing or anticipating partial bits of information; and finding
and separating similar items by detecting small differences.
These properties, which underlie both its efficiency and popu-
larity, echo the abilities of the memory systems operating in
our own brains, particularly the episodic memory circuits depen-
dent on the hippocampus (Squire et al., 2004; Tulving, 2002). The
hippocampus is crucial for the encoding of memory, it is adept at
integrating and interpreting contextual cues to drive recall, and it
is efficient at both discrimination and association (Maren et al.,
2013). Thus, much like how Google works as an index of informa-
tion, one parsimonious explanation for hippocampal function is
that it functions as an index of memories (Guo et al., 2018; Miller
and Sahay, 2019; Tanaka, 2020; Tanaka and McHugh, 2018;
Tanaka et al., 2018; Tonegawa et al., 2018). This is not a new
idea (McClelland et al., 1995; Teyler and DiScenna, 1985,
1986; Teyler and Rudy, 2007); however, recent work has begun
to lend direct experimental evidence to this theory and edifying
putative, underlying circuit mechanisms. Here, we will explore
and examine these findings in depth and discuss possible index-
ing mechanisms, as well as how these ideas could shape a better
understanding of memory processes in both the healthy and
diseased brain.
The discovery of place cells, neurons in the hippocampus that
have receptive fields tuned to discrete locations within a context
(O’Keefe and Dostrovsky, 1971), revolutionized the experimental
approach to studying hippocampal function (Moser et al., 2017).
One of the earliest and most influential theories to emerge linking
place cell activity and episodic memory was the cognitive map
theory (O’Keefe and Nadel, 1978), positing that the primary
role of the hippocampus is to provide a spatial framework that
permits the location and association of the items and events
that constitute a given experience. While the authors suggested
that this cognitive map may not be limited to physical space and
could be applied to map episodic experience more broadly,
place cells and their properties have proved a useful substrate
to examine and test these ideas. For example, as different en-
sembles of neurons are recruited to represent different spatial
experiences, the hippocampus could continuously provide a
new underlying scaffolding across space (and time) that would
allow memories to remain both related and distinct. Subsequent
retrieval could then be triggered by a reinstatement of the original
spatial map triggered by the cues that define a given context (Wi-
kenheiser and Redish, 2015). Over time, other theoretical models
have built on and expanded these ideas, and, as noted in other
sections below, have proposed anatomical substrates for hippo-
campal functions that include novelty detection (Lisman and Ot-
makhova, 2001; Vinogradova, 2001), rapid encoding, and
pattern completion and separation (Kesner and Rolls, 2015;
Knierim and Neunuebel, 2016; Nadel and Moscovitch, 1997),
as well as their relation to spatial coding. Moreover, frameworks
that encompass the place cell data but are not tied to a specific
spatial function of the hippocampus have also been described.

Neuron 107, September 9, 2020 ª 2020 Elsevier Inc. 1

 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
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These posit that place cells may reflect a broader functionality
related to general-purpose sequence generation (Buzsáki and
Tingley, 2018) or relational memory (Cohen and Eichenbaum,
1993; Eichenbaum et al., 1994), allowing the extension of both
hippocampal memory and physiology (Aronov et al., 2017; Mac-
Donald et al., 2011; Pastalkova et al., 2008) beyond the domain
of physical space.
Hand in hand with the growing characterization of place cell
physiology, there developed a deeper understanding of the
anatomical, behavioral, and computational properties of the hip-
pocampal circuit. This resulted in specific mnemonic functions
being linked to the anatomic and physiological properties of
discrete subregions of the structure (Fanselow and Dong, 2010;
Nadel et al., 2013; Strange et al., 2014). In this framework, the
classic model of sequential processing along the trisynaptic
loop has the large number and sparse activity of granule cells in
the dentate gyrus (DG) providing orthogonalization of similar
cortical inputs leading to pattern separation (Hainmueller and Bar-
tos, 2020; Leal and Yassa, 2018; McHugh et al., 2007), the DG
providing input to the recurrent CA3 network to facilitate autoas-
sociation and pattern completion (Cayco-Gajic and Silver, 2019;
Kesner and Rolls, 2015; Knierim and Neunuebel, 2016; McHugh
et al., 2007; Nakazawa et al., 2002), and finally, CA1 broadcasting
the results back to the cortex (Soltesz and Losonczy, 2018; Valero
and de la Prida, 2018). This framework has served as the back-
bone of relating place cell activity to memory processing, insofar
as place cells may coordinate the pattern separation, completion,
and reinstatement properties noted above.
Building on this framework, advances in genetic approaches
have led to activity-dependent memory tagging systems in
rodent models, which allow for the examination and artificial re-
activation or inhibition of distinct memory traces (Josselyn and
Tonegawa, 2020). These traces fulfill the properties of the mem-
ory engram, a moniker for the physical basis of memory first pro-
posed by zoologist and biologist Richard Semon (Schacter et al.,
1978; Semon, 1921), in that they can be viewed as the physical
instantiation of an experience registered in enduring changes
in synaptic connectivity and physiology of an ensemble of
neurons. Tagging systems employed include the tetracycline-
regulated transcriptional activation system, in which time-locked
expression of actuators such as opsins or chemogenetic recep-
tors are induced via activity-dependent promoters (e.g., c-Fos-
or Arc-expressing; Liu et al., 2012) or immediate early gene
(IEG)-binding elements (Sun et al., 2020), as well as the Cre-
ERT (estrogen receptor T2) transcription system (targeted
recombination in active populations [TRAP] mice), which utilizes
a tamoxifen-sensitive modified estrogen receptor to drive expe-
rience-driven expression of Cre-dependent constructs in acti-
vated cells (Guenthner et al., 2013). Such methods have allowed
for the artificial triggering of memory-related behavior even in
contexts where no such behavior would be expected. While
these methods are not without their caveats (discussed further
in sections below), engram-labeling studies have shown that op-
togenetic or chemogenetic stimulation or inhibition of excitatory
neurons in the DG (e.g., Guo et al., 2018; Lacagnina et al., 2019;
Liu et al., 2012), CA3 (e.g., Denny et al., 2014), or CA1 (e.g.,
Ghandour et al., 2019; Ryan et al., 2015; Tanaka et al., 2014) re-
instates or impedes (respectively) behavioral recall of that expe-
2 Neuron 107, September 9, 2020
Perspective
rience. While many engram studies have focused on measures
of conditioned fear, these and other studies report hippocampal
engram-driven behavior for a variety of context-specific behav-
iors, including place (e.g., Ramirez et al., 2013) or social avoid-
ance (e.g., Zhang et al., 2019), as well as appetitive conditioning
and place preference (e.g., Redondo et al., 2014).
These findings raise several key questions. First, how can a
small number of experience-tagged hippocampal engram cells,
much fewer in fraction than that of active place cells (e.g., Tanaka
et al., 2018), encode a complex behavioral experience? Indeed,
activation of a very small percentage (2%–3%) of DG granule
cells labeled during learning can reproduce context-appropriate
behaviors (for examples, see Liu et al., 2012). Further, activation
in the DG could harness the pattern completion abilities of the
downstream CA3 network to amplify their activity via attractor
dynamics (Colgin et al., 2010; Knierim and Neunuebel, 2016)
and lead to a robust brain-wide reinstatement of a memory-
related ensemble. However, reactivation of a subset of CA1
neurons, which lack recurrent connectivity, can also trigger
behavioral reinstatement and presumably memory recall (e.g.,
Ryan et al., 2015). It is plausible that downstream activation of
the entorhinal cortex (EC) and/or re-entrant excitation of the
DG and CA3 add these features, thereby functioning like a recur-
rent network, although experimental evidence supporting this
interpretation is lacking.
Additionally, 50 years of hippocampal physiology in rodents
has revealed that place cell activity is exquisitely structured
across not only space but also time (Howard and Eichenbaum,
2015). During exploration, the dominant theta oscillation in the
hippocampal local field potential (LFP) organizes ensembles of
place cells with spatially adjacent receptive fields into se-
quences, expressed on the timescale of a single theta cycle of
125 ms (Burgess and O’Keefe, 2011). These sequences can
be re-expressed during sharp-wave ripples (SWRs) that occur
during pauses in movement on an even shorter timescale, com-
pressed into fast events lasting only 10s of milliseconds (Foster,
2017). This precise temporal arrangement of activity has made
the gap between place-cell- and engram-based memory studies
difficult to bridge, as the latter have demonstrated that
simultaneous optogenetic activation of ensembles of neurons
in temporal and spatial patterns that are not observed under nat-
ural physiological conditions are sufficient to evoke behaviors
mimicking memory recall. One can interpret this gap in the tem-
poral dynamics between optically induced behavioral reinstate-
ment and place cell activity as reflecting the dispensability of
these temporal pattern for behaviors driven by contextual recog-
nition, or perhaps this disconnect could simply be due to tech-
nical limitations in the place cell recording, as the retrieval of a
hippocampal-dependent memory can occur very rapidly and in
the absence of the exploration needed to drive extensive place
cell activity, precluding a robust sampling of activity. For
instance, when rodents receive a footshock immediately after
placement in a previously exposed chamber, context explora-
tion may be minimal, yet animals successfully retrieve the
contextual memory and associate it with shock, resulting in
context-dependent behavior during subsequent memory tests
(Wiltgen et al., 2001). One possibility is that reinstatement of
even a single place field is sufficient for memory reinstatement.
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
Perspective
Figure 1. Comparing and Contrasting Hippocampal Place Cells and
Engram-Tagged (Immediate Early-Gene-Expressing) Neurons
Place cell activity has precise temporal structure during both exploration and
rest, whereas engram-tagged neurons are simultaneously and experimentally
reactivated. Place cell density appears moderate, and this density of active
place cells is relatively stable in any given context. Conversely, engram-tagged
cells in the hippocampus are sparse, with familiar contexts exhibiting low
levels of tagged expression. Engram cells exhibit considerably less stability in
their context-dependent reinstatement over time as compared to place cells,
although both are highly unstable with time. Remote time points for re-
activation of experience-dependent engram cells remain unknown. While
there are overlapping behavioral correlates of place and engram cell activity,
place cell research has led the field in its correlation to behavior.
However, long-term monitoring of the stability of place cell
representations across repeated visits on the timescale of
weeks, now possible due to advances in in vivo imaging ap-
proaches in mice, suggests that there exists a hitherto unappre-
ciated high degree of instability in the spatial representation of a
familiar environment (Ziv et al., 2013; but, also see (Gonzalez
et al., 2019). If only a fraction (15%) of place cells show stability
ll
across several weeks, it becomes more difficult to draw a direct
connection between memory recall and a completely stable
spatial representation. It is possible that a small fraction of stable
place cells can serve as a partial cue to reinstate the full repre-
sentation of memory through a process of pattern completion
in downstream regions; however, this view is challenged by a
recent study examining the physiological nature of engram cells
in the hippocampus, which is discussed below (Tanaka et al.,
2018). Thus, while place cell studies have provided insight into
the anatomical organization and potential memory mechanisms
of the hippocampus, we, like many others, struggle to reconcile
these potential spatial coding properties with the core role of the
system as a memory storage device (Tanaka, 2020). Further, it is
important, both through hypothesis and experiments, to attempt
to identify the rules of transformation that allow simultaneous
activation of hippocampal engrams to generate appropriate pat-
terns of downstream activation and behavior (Lisman et al.,
2017). Perhaps then, we should reconsider what the activity of
hippocampal neurons during memory formation and recall truly
represents and how place cells that have driven much of the
thinking in the field for the last 50 years can inform us about
the hippocampus as a memory system (Figure 1).
Instantiating the Hippocampal Index
The hippocampal memory indexing theory posits that the hippo-
campus does not ‘‘contain’’ the episodic memory itself; rather, it
generates a code or ‘‘index’’ that binds neuronal activity patterns
underlying an experiential event, which is stored across distrib-
uted neocortical (and potentially subcortical) modules (Teyler
and DiScenna, 1985, 1986; Teyler and Rudy, 2007). In other
words, the hippocampus encodes a linked representation of
brain activity at the time of an experience or episode, which
can subserve subsequent recall via activation of that hippocam-
pal representation. What is presumed to make these patterns of
activity unique from other experience-induced patterns in the
brain, such as ensemble activity in the sensory cortex activated
by a stimulus, is their conjunctive and associational nature and
the ability of the hippocampal ensemble to reinstate the original
spatial and temporal patterns of cortical/subcortical activity of an
experience (McClelland et al., 1995; Teyler and Rudy, 2007).
Important to note is that the indexing theory is not mutually
exclusive to the cognitive map theory. Instead, it simply remains
agnostic to what, if anything, the hippocampal neurons involved
in memory indexing must represent in terms of behaviorally rele-
vant information; spatial coding would be acceptable if these
neurons had properties consistent with that of an index, as sum-
marized and presented in Figure 2. In the following and subse-
quent sections, we elaborate on these features and discuss
how the brain’s circuit architecture supports a view of hippocam-
pal function through the lens of indexing.
Engrams as Indices
Numerous studies have now shown that photoactivation of a
sparse hippocampal engram drives IEG activity in select down-
stream brain regions thought to be involved in the original
learning (e.g., Ramirez et al., 2013, 2015; Roy et al., 2017).
Such observations, together with the reinstatement of behavior
following optogenetic engram stimulation, support the idea
that the hippocampus is capable of indexing and triggering
Neuron 107, September 9, 2020 3
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
ll
memory recall by reinstating learning-dependent activity in
memory-related extrahippocampal brain systems. However,
increased IEG induction in extrahippocampal structures
following artificial activation of engram-bearing hippocampal
cells does not necessarily indicate that these are the precise ex-
trahippocampal neurons involved in the original learning. More-
over, specific controls, such as untagged, context-exposed
and nonreinforced animals, are often essential to address issues
of memory versus performance; indeed, animals may be able to
use alternative learning or generalization strategies to achieve
task-dependent behavior (e.g., Wiltgen et al., 2010), even in
the absence of the hippocampus (for discussion, see Maren
et al., 2013). So, what is the evidence for learning-specific and
hippocampus-dependent reinstatement of neural activity? To
this end, one study has shown that photoinhibition of learning-
tagged CA1 pyramidal cells resulted in the reduction of fear
behavior in a shock-associated context and that this coincided
with reduced reinstatement of c-Fos expression, specifically in
other c-Fos-tagged and, presumably, engram-bearing cortical
and subcortical cells of the brain (Tanaka et al., 2014). In a sepa-
rate study (Guo et al., 2018), it was found that contextual fear
4 Neuron 107, September 9, 2020
Perspective
Figure 2. Key Features of Hippocampal
Memory Indexing Theory
learning increased mossy fiber synaptic
contacts of tagged engram-bearing den-
tate granule cells (DGCs) with parvalbu-
min-positive (PV+) stratum lucidum inhib-
itory neurons (SLINs) to a significantly
greater extent than a random population
of DGCs. This engram-dependent
recruitment of PV+ SLINs returned to
pre-learning levels with time-dependent
memory generalization. By genetically
enhancing the coupling of engram-
bearing DGCs with PV+ SLINs, the au-
thors increased feed-forward inhibition
in DG-CA3 circuitry and stabilized the
hippocampal engram. Critically, this was
shown to confer optogenetic behavioral
reinstatement and context-specific reac-
tivation of a distributed fear memory trace
in hippocampal-cortical-subcortical net-
works at remote time points. Collectively,
these findings mirror natural recall, inso-
far as contextual fear memory retrieval
in the original learning context is associ-
ated with the specific reactivation of
learning-dependent tagging in the hippo-
campus and some extrahippocampal tar-
gets. However, formal demonstration for
how hippocampus may in fact coordinate
extrahippocampal reinstatement in an
experience-dependent manner is absent.
In light of understanding hippocampal
engram functions through the lens of in-
dexing, it is important to emphasize that although behavioral
reinstatement does not equate to neural reinstatement, the
behavioral outcomes of optogenetic manipulations of hippo-
campal engrams appear experience dependent. For example,
as noted above, stimulation of contextual fear-conditioning-
tagged cells in the DG results in increased freezing in a safe
(no shock) context (e.g., Liu et al., 2012). However, if such stim-
ulation of the DG occurs for neurons that were tagged following
the extinction of fear in a shock-associated context, then this
manipulation results in reduced freezing in a shock-associated
context and decreased spontaneous recovery of contextual
fear (Lacagnina et al., 2019). Likewise, inhibition of context-
fear-tagged DG cells attenuates freezing in a shock-associated
context (Tanaka et al., 2014), but inhibition of extinction-tagged
DG cells can increase defensive responding in a previously extin-
guished context (Lacagnina et al., 2019). These experience-spe-
cific findings are complemented by other studies where the
behavioral response (beyond defensive behavior) of DG engram
reactivation reflects the valence of the reinforcing stimuli associ-
ated the context or engram (e.g., Ramirez et al., 2015; Redondo
et al., 2014). Also, consider that simply reactivating engram cells
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
Perspective
that were tagged during homecage exploration or exposure to a
context in which shock never occurred does not appear to
induce abnormal locomotion or overt defensive behaviors (e.g.,
Ghandour et al., 2019).
While indexing may explain the capacity for photoactivation of
tagged hippocampal engram cells to trigger memory-specific
behavior in different contexts, reinstatement of behavior is often
notably less than what would be expected through natural recall
(i.e., returning the animal to the original training context). In the
framework of indexing, we propose there are number of reasons
why this may be the case beyond the fact that natural recall is
presumably most effective in reactivating the index. Importantly,
the abovementioned tagging systems, while experimentally time
locked, are still thought to open a window of tagging that may be
on the order of at least several hours. Thus, when artificially reac-
tivating these cells, it is possible that the experimenter may also
be triggering activation of other nonspecific indices and/or
experiences such as activity in the homecage and pre- or
post-training handling. These patterns are not specific to the pri-
mary learning episode in question and thus may compete for
behavioral expression. Contextual stimuli present in the test
context may also trigger interference as well, acting as external
inhibitors. Thereby, a number of controls (e.g., nonreinforced,
homecage) for better isolating and assessing the degree of
experienced-dependent behavioral reinstatement should be
performed. Additionally, hippocampal indices not only are pro-
posed to encode the relevant brain systems activated during
an experience but also may represent the sequential patterns
of such activation (Buzsáki and Tingley, 2018). Current methods
of optogenetic reactivation of hippocampal engram cells lack
such sequence-based reactivation (Carrillo-Reid et al., 2019),
beyond what is inherently structured in the linkage of hippocam-
pal engram-bearing circuits. Further technological advance-
ments, which may better constrain the window of tagging to a
particular experience or may be able to reactivate cells in
sequence-dependent manners, are crucial to improve the read-
outs and interpretation of this reinstatement.
Is the hippocampus alone in its potential capacity for index-
ing? Association cortices such as the sensory association cortex
and EC may also exhibit indexing properties due to their conver-
gence of sensory input, thereby contributing to a hierarchical in-
dexing scheme (McClelland et al., 1995). Thus, the hippocampus
may serve to some extent as an index of indices in the EC and
other input structures as information is routed in and then back
out again. Assuming such hippocampal signals can be decom-
pressed to reinstate activity in cortical and subcortical nuclei
(as noted above), an exact one-to-one representation in the hip-
pocampus of cortical modules (for example) seems unlikely and
may not be necessary. In fact, convergence of neural activity into
the hippocampus might be essential for its abilities to form
conjunctive contextual representations (Rudy and O’Reilly,
1999). Other critical targets of the hippocampus, such as the ret-
rosplenial cortex (RSC) (Cowansage et al., 2014; Mao et al.,
2018) or lateral septum (LS) (Bender et al., 2015; Besnard
et al., 2019; Tingley and Buzsáki, 2018), may also maintain
such convergence of processing and may thereby be part of a
hierarchical indexing scheme, assuming these structures are
capable of reinstating patterns of experience-specific assembly
ll
patterns. Indeed, one study found that reactivation of cells of the
RSC that were tagged at conditioning is sufficient to induce
behavioral expression of fear, even in the absence of a fully func-
tional hippocampus (Cowansage et al., 2014). Importantly, this
study showed that optogenetic activation of the RSC engram,
like natural recall, recruited overlapping downstream circuits in
the amygdala and EC, demonstrative of reinstatement of experi-
ential activity. Thus, indexing may not necessarily be unique to
the hippocampus; however, the hippocampus may be uniquely
positioned to index episodic events, given the significantly
greater extent to which it integrates complex and hierarchical
sensory information from across the brain (see sections below),
as well as due to its discriminative coding and circuit architec-
ture. Unpublished findings indicating that reactivation of
engram-tagged neural structures, outside the hippocampus,
does not equally reinstate behavior may support the particular
importance of hippocampal indexing (Roy et al., 2019).
Memory Indexing in Humans?
Electrophysiological studies in humans have suggested that the
human hippocampus also possesses properties consistent with
indexing. For example, in epileptic patients with depth elec-
trodes implanted into the medial temporal lobe, free recall of
an audiovisual experience was shown to follow the selective re-
activation of hippocampal and EC cells that were active during
the prior experience (Gelbard-Sagiv et al., 2008). Likewise,
successful retrieval in an object association task coincided
with reinstatement of spiking activity in hippocampal and EC
cells, hippocampal activity preceding EC firing, and decoding
analyses of EC activity predicting the identity of the recalled ob-
ject (Staresina et al., 2019). Other intracranial recordings have
shown that behavioral recall was linked to coordinated hippo-
campal-lateral temporal cortical representational reinstatement
of item-context associations (Pacheco Estefan et al., 2019). In
this study, hippocampal reinstatement preceded that seen in
the neocortex, and hippocampal-cortical gamma phase syn-
chrony during hippocampal reinstatement predicted neocortical
reinstatement. Moreover, these findings are mirrored in addi-
tional studies that have found memory-related reinstatement in
the human hippocampus is underscored by a sparse and distrib-
uted set of active cells (Wixted et al., 2014, 2018).
Human functional magnetic resonance imaging (fMRI) studies
support a similar interpretation. For example, one fMRI study
(Harand et al., 2012) reported that hippocampal BOLD (blood-
oxygen-level-dependent) activity during an episodic learning
experience matched its activity at recall (i.e., recognition of pre-
viously shown visual cues), particularly when subjects reported
the remembering of episodic details of the learning event. Inter-
estingly, this episodic reinstatement of hippocampal activity
occurred for remembered cues at 3 days and even 3 months
following learning. Moreover, for successful retrieval of experien-
tial memory (in tasks such as object recall and recognition),
regions including the RSC, parahippocampal cortex (PHC), peri-
rhinal cortex (PRC), and prefrontal cortex (PFC) have all been
shown to exhibit recall-dependent reinstatement along with or
in close temporal proximity to hippocampal reinstatement, sug-
gestive of hippocampal-dependent routing (e.g., Arnold et al.,
2018; Jonker et al., 2018; Schultz et al., 2019). Again, while rein-
statement and temporal patterns of activation alone do not
Neuron 107, September 9, 2020 5
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10.1016/j.neuron.2020.07.011
ll
Figure 3. Hippocampal (DG-CA3-CA2-CA1) Circuit Architecture and
Anatomical Loops Permit Flexible Integration and Routing of
Experiential Information
(A) Examples of hippocampal inputs (blue arrows).
(B) Examples of hippocampal outputs (orange arrows). Note that the pro-
jections shown are not exhaustive.
Brain regions include the anterior cingulate cortex (ACC), bed nucleus of the
stria terminalis (BNST), basolateral/basomedial amygdala (BLA/BMA), central
amygdala (CEA), dentate gyrus (DG), dorsal raphe nucleus (DRN), entorhinal
cortex (EC), cornu ammonis regions (CA1–CA3), infralimbic cortex (IL), locus
coeruleus (LC), anterior/lateral hypothalamic area (A/LHA), lateral septum (LS),
medial septum (MS), nucleus accumbens (NAC), orbital frontal cortex (OFC),
prelimbic cortex (PL), nucleus reuniens (RE), retrosplenial cortex (RSC), sub-
iculum (SUB), supramammillary nucleus (SUM), and ventral tegmental area
(VTA). Brain region images were generated using Brain Explorer 2.0 (Lein
et al., 2007).
demonstrate indexing, these findings are consistent with data
from rodents and leave open the possibility that future experi-
ments may directly test this idea in humans.
6 Neuron 107, September 9, 2020
Perspective
An Integrated Circuit Model of the Hippocampal Index
In the decades since the introduction of the hippocampal mem-
ory indexing theory, considerable advances have been made in
our understanding of the complexity and diversity of hippocam-
pal circuits. If experience-tagged hippocampal engrams serve
as episodic indices, how might the circuit architecture of the
brain be employed for encoding and recall? To these ends,
the conjunctive, sparse, and compressed code generated in
the DG via pattern separation would support indexing by mini-
mizing memory interference (Figure 2, feature i) (Cayco-Gajic
and Silver, 2019; Hainmueller and Bartos, 2020; Knierim and
Neunuebel, 2016; McHugh et al., 2007), while DG outputs,
together with direct EC inputs (alongside the diverse afferents
described below), onto CA3 cells would bias attractor dynamics
in the recurrent network to store an experience as a new mem-
ory, or catalyze the retrieval or updating of a previously encoded
memory by pattern completion (Figure 2, features ii–iv). Accord-
ingly, the experience is registered in a sparse hippocampal code
or engram composed of principal cells (and inhibitory neurons
[INs]) across the different subregions (DG, CA3, CA2, and
CA1), with their coordinated activity permitting intra- and extra-
hippocampal reinstatement of the original experience through
dynamic routing (Figure 2, features v–vii; Figures 3 and 4). We
elaborate on this idea with recent examples in the next sections.
Dynamic Routing: Hippocampal Afferents
In this framework, the DG-CA3-CA2-CA1 circuit can be perceived
as a template of nodes, with each node receiving diverse intra- and
extrahippocampal inputs allowing for the integrative, dynamic,
and flexible incorporation of cognitive and visceral information
into memory representations (Figure 3A). These properties would
enable the hippocampus to participate in many ‘‘types’’ of mem-
ories—spatial, goal-oriented, social, future-planning—all which
may comprise diverse episodic experiences. For example, direct
long-range GABAergic projections from the lateral hypothalamus
(LH) to CA3 have been recently identified (Zhou et al., 2019a);
these neurons synapse onto CA3 interneurons and appear to
have critical functions in tasks of object recognition and discrimi-
nation, revealing a direct pathway by which CA3 may integrate
endocrine signals in learning and memory processes. CA3 neu-
rons also incorporate locus coeruleus (LC) input, and one study
found that LC projections to dorsal CA3 (dCA3; but not to CA1
or DG) are required for encoding (but not retrieval, which may be
mediated by CA3-CA1 [see below]) of a contextual representation
(as assessed by distance traveled in a previously explored context
or via single-trial contextual fear conditioning) (Wagatsuma et al.,
2018). Additionally, parallel circuits projecting from neurons in
the supramammillary nucleus (SUM) to the DG and CA2 have
been found to carry contextual and social novelty signals, respec-
tively, allowing hypothalamic sculpting of hippocampal memory in
a task-specific manner (Chen et al., 2020; see also Li et al., 2020;
Hashimotodani et al., 2018). These recent discoveries broaden our
understanding of the diversity of mammalian hippocampal affer-
ents and point to multiple sources via which the hippocampus
may integrate signals for memory formation or recall. Activity of
these distinct sets of inputs (alongside other important inputs,
including from the amygdala and anterior cingulate cortex), re-
cruited based on ongoing experience, may govern which hippo-
campal routes are deployed for encoding and/or recall.
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
Perspective
Dynamic Routing: Hippocampal Efferents
Further arguing against a simple sequential processing loop, it is
clear that each node within the DG-CA3-CA2-CA1 circuit pro-
jects to distinct outputs (Figure 3B). In the framework of index
theory, these outputs may be flexibly deployed by engram cells
to reinstate an experience (whether that experience is appetitive,
aversive, etc.). An example of this potential selective routing can
be found in ventral CA1 (vCA1) neurons (Ciocchi et al., 2015). In
this study, vCA1 cells were tracked based on their projections to
the PFC, nucleus accumbens (NAc), and amygdala during
behavior, revealing that activity in these neurons were task and
pathway dependent. These findings critically suggest that sig-
nals out of CA1 are not uniformly transmitted to its targets;
rather, it supports the idea of that efferent hippocampal signals
are routed based on task and mnemonic demands. With partic-
ular relevance to indexing, dorsal CA1 (dCA1) tetrode recordings
paired with circuit-specific optogenetics have shown that
expression of conditioned place preference (CPP) depends on
the reinstatement of dCA1 representations that were active dur-
ing training (Trouche et al., 2019). Furthermore, CPP expression
is lost if dCA1 terminals in NAc are photoinhibited, despite dCA1
pyramidal cells maintaining their context-dependent cell assem-
blies during testing (see also Zhou et al., 2019b).
This routing ability is not restricted to CA1; CA3 output neu-
rons may route information via projections to CA1, CA2, or the
DLS (dorsolateral septum). Indeed, brain-wide analyses of co-
activated circuits accompanying contextual fear discrimination
identified a CA3-DLS module (Besnard et al., 2019). This
pathway appears to recruit somatostatin (SST)+ DLS cells to
gate conditioned freezing, as in vivo calcium imaging found
SST+ DLS cell activity reliably discriminated shock-associated
versus safe contexts. In support of these findings, optoge-
netic-terminal-specific silencing of dCA3 terminals in dCA1
and DLS has suggested distinct roles for dCA3-CA1 and
dCA3-DLS projections to contextual fear learning (or consolida-
tion) and discrimination, respectively (Besnard et al., 2020).
For CA2, its efferent network positions it strongly for memories
involving social recognition, discrimination, and aggression (Mid-
dleton and McHugh, 2019). Indeed, CA2 (and CA3) efferents do
not uniformly regulate discrimination (Raam et al., 2017). Optoge-
netic experiments have demonstrated that anterior CA2/dCA2
neurons targeting dCA1 are essential for novel object recognition,
but not for discrimination between novel and familiar conspecifics.
The opposite was true for dCA2/dCA3 projections to posterior
CA1. Photoinhibition of dCA2/dCA3 projections to the DLS were
instead shown to somewhat enhance social discrimination, but
with no effect on object discrimination or recognition. In social be-
haviors, axons from dCA2 neurons targeting ventral hippocampus
were shown to be critically involved in maintaining memory of a
familiar animal (Meira et al., 2018; Raam et al., 2017), while phar-
macogenetic inhibition of CA2 terminals in the DLS attenuates so-
cial aggression (Leroy et al., 2018), a pathway that, when active,
appeared to invoke DLS-innervation of the ventromedial hypothal-
amus to drive attack behavior.
In total, multiple nonoverlapping engrams within these diverse
hippocampal routes may compete through updating or ongoing
learning to modify behavioral output. For example, two-photon
(2P) imaging of DG and CA3 engrams in vivo revealed that the
ll
updating of a reward location promoted activity remapping in
CA1 and CA3, but not in the DG (Hainmueller and Bartos,
2018). Recent work has also demonstrated that contextual fear
extinction recruits a distinct DG engram from that encoding the
original context-shock association, which reduces levels of
freezing in the training context but can be overcome by the orig-
inal engram to induce relapse (Lacagnina et al., 2019). Likewise,
prolonged optogenetic or chemogenetic reactivation of a DG
fear memory engram in the training context without the uncondi-
tioned stimulus promoted extinction of the conditioned response
(Khalaf et al., 2018). Of course, the hippocampus is not unique in
this type of broad connectedness; other hubs in the brain,
including the claustrum (Jackson et al., 2020) and the thalamus
(Halassa and Sherman, 2019), may surpass it in terms of total
connectivity. However, these data suggest that the hippocam-
pus is capable of integrating and routing complex information
from a variety of source structures, supporting its role in the bind-
ing of cognition and emotion to subserve memory (Figure 4A).
Dynamic Routing: Inhibitory Microcircuits
How might these diverse communication channels running
through the hippocampus be managed? Hippocampal INs are
well positioned to function as arbiters of information flow in the
hippocampus, as they target different cellular compartments of
principal neurons, are reciprocally connected with other interneu-
rons, and project locally within and across different subregions
and lamellae and out of the hippocampus to association cortices
and subcortical circuits (long-range INs) (Caroni, 2015). Moreover,
hippocampal INs modulate neuronal excitability, summation of
excitatory inputs, and neuronal firing in addition to generation of
network oscillations (theta and gamma oscillations) and as such
are thought to play critical roles in local circuit computations un-
derlying exploration and encoding, action selection, memory
consolidation, retrieval, and reinstatement (Cardin, 2018; Makino
et al., 2019; Roux and Buzsáki, 2015; Sosa et al., 2018). Indeed,
recent studies have uncovered a diverse population of INs in
CA1 and CA3 that exert perisomatic and dendritic inhibition on
DGCs and are modulated by SWRs.
Local INs may regulate information flow within a hippocampal
subregion by biasing recruitment of principal cells, thereby
creating parallel channels as evidenced in a study that identified
biased PV+ basket cell (BC) connectivity with deep and superfi-
cial CA1 neurons of the ventral hippocampus (Lee et al., 2014).
The authors found that PV+ BCs preferentially innervated deep
CA1 pyramidal neurons but received greater excitatory inputs
from superficial CA1 pyramidal neurons. At the level of output,
PV+ BCs exert greater inhibition onto basolateral amygdala
(BLA)-projecting deep CA1 neurons than those that projected
to the PFC and, in turn, received greater excitatory input from
PFC than BLA. These data suggest that PV+ BCs do not uni-
formly inhibit CA1; instead, it is likely that PV+ BC-principal cell
microcircuits bias information flow to distinct vCA1 outputs,
including PFC, BLA, NAc, DLS, and LH (serving dynamic and
flexible routing). Local INs may also differentially regulate theta
phase-locking and burst firing of CA1 neurons through somatic
or dendritic inhibition, respectively (Royer et al., 2012). Because
burst firing of pyramidal cells is thought to increase synaptic
communication by increasing excitation of downstream targets,
local INs may modulate CA1 outputs through this mechanism
Neuron 107, September 9, 2020 7
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10.1016/j.neuron.2020.07.011
ll
A Figure 4. Hippocampal Engrams May Index
B (Basu et al., 2016). This disinhibition of
(Graves et al., 2012; Lisman, 1997; Takahashi and Magee, 2009).
Importantly, rhythmic optogenetic activation of PV+ INs in CA1 to
mimic that seen during learning enhanced theta, delta, and ripple
oscillations; stabilized functional connectivity between CA1 neu-
rons; and reliably promoted ensemble reactivation (Ognjanovski
et al., 2014). The exact role these oscillations play in the ability of
an index to reactivate downstream targets remains largely un-
tested; however, evidence suggests the coherence or coordina-
tion of activity they provide may facilitate both the encoding and
recall of memories across various structures by ensuring tempo-
ral coordination of activity (Buzsáki, 2015; Corcoran et al., 2016;
Igarashi et al., 2014; Joo and Frank, 2018; Lin et al., 2017; Ma-
kino et al., 2019; Wirt and Hyman, 2019).
Pioneering in vivo recordings and imaging studies in rats identi-
fied extensively connected INs with extrahippocampal (septum,
subiculum, para- and pre-subiculum, and RSC) projections that
coordinate network oscillations (Bonifazi et al., 2009; Jinno,
2009). Long-range inhibitory projection neurons of the LEC sup-
8 Neuron 107, September 9, 2020
Perspective
Experience to Reinstate Experiential
Memory
(A) Distinct experiences are thought to be encoded
within DG-CA3-CA2-CA1 connections, with
engram-bearing cells being functionally linked to
other neurons for the same episode. Recall can
then be driven by partial input (cues) that reinstate
activity (filled-in circles/squares) within hippo-
campal circuits to drive extrahippocampal rein-
statement via its diverse outputs and connectivity
to other engram-bearing cells. PCs, principal cells;
INs, inhibitory neurons.
(B) Hippocampal cells may register more than one
experience in distinct patterns of connectivity
prescribed by activity-dependent gene expres-
sion (shown here as combinations of 1 s and 0 s).
press CA1 cholecystokinin-positive
(CCK+) interneurons that relay feed-for-
ward inhibition from CA3 to CA1 ex vivo
CA1 interneurons induced enhanced den-
dritic spiking within a specific temporal
window, a mechanism by which sensory
information and mnemonic information
arriving from excitatory LEC inputs and
CA3, respectively, may be integrated.
More recently, a class of long-range inhib-
itory neuronal nitric oxide synthase
(nNOS)-expressing cells in CA1 (LINC neu-
rons) has been identified that project both
locally and extra-hippocampally (Christen-
son Wick et al., 2019). These neurons
inhibit superficial and deep principal cells
and other INs in CA1 and project
to diverse extrahippocampal targets,
including the tenia tecta, subiculum, hypo-
thalamus, olfactory bulb, and EC. Optoge-
netic activation of LINC neurons entrained
hippocampal oscillations and hippocam-
pal-frontal cortex (tenia tecta) coherence.
Thus, converging evidence has begun to illuminate how cell phys-
iology, activity-dependent gene expression, and microcircuit con-
nectivity support hippocampal engram-cell-dependent indexing
(i.e., encoding of experiences and routing of information to mediate
reinstatement). We discuss these features of engram cell iden-
tity next.
Index Cell Identity
Given the long-standing focus on rodent hippocampal place
cells, an obvious question is what aspect of contextual memory
is encoded within the hippocampal engram. Behavioral studies
using variations of contextual fear conditioning suggest that
the hippocampus generates a conjunctive representation of
multimodal sensory information formed through physical explo-
ration of a context (Fanselow, 2000; see also Krasne et al., 2015).
For example, one study preexposed rats to either the condition-
ing context or independent features of that context and found
context fear after an immediate shock is facilitated only when
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
Perspective
these multimodal cues are presented together, suggesting that
the hippocampus represents the conjunction of the cues
defining the context (Rudy and O’Reilly, 1999). Indeed, tempo-
rary pharmacological inactivation of the hippocampus during
the context preexposure prevents the contextual fear condition-
ing of immediate shock (Matus-Amat et al., 2004). Past studies of
IEG expression in the hippocampus support this this view (e.g.,
Huff et al., 2006; Zhu et al., 1997); the strongest IEG response
is achieved when a novel combination of multimodal cues is pre-
sented to the animal. Conversely, hippocampal IEG expression
is weak or nonexistent when a highly habituated stimulus is
given. Note that immediate shock upon context entry in the
absence of preexposure (and extensive postexposure) does
not appear to elevate levels of IEGs in the hippocampus relative
to a habituated homecage (see also Erwin et al., 2020). These
data suggest that IEG-expressing engram neurons may not
necessarily or exclusively store spatial information, as rodents
will have active place cells even in the most familiar of contexts,
but rather hippocampal circuits detect novelty in the combina-
tion of sensory cues and encode it as a contextual representation
supporting the episodic experience. Indeed, optogenetic stimu-
lation of CA1 neurons tagged in a novel context the day prior to
immediate shock delivery in the same context, but not a different
context, resulted in retrieval of the contextual fear memory
(Ghandour et al., 2019; see also Ramirez et al., 2013). Thus, a
memory engram, defined by active principal cells during contex-
tual learning, may preferentially encode conjunctive contextual
information, as opposed to specific locations that could be
biased by a specific cue or subset of cues.
Physiology
Key insights into the precise identity of engram-bearing cells
came from in vivo recording of CA1 neurons in a mouse in which
c-Fos-positive neurons labeled during a novel context exposure
were tagged with channelrhodopsin 2 (ChR2) and subsequently
optically identified (Tanaka et al., 2018). As expected, 50% of
all CA1 pyramidal cells could be classified as place cells; however,
only one-quarter of these place cells also expressed c-Fos (opto-
genetically identified). In short, engram cells were place cells, but
only one-quarter of place cells were engram cells. During memory
encoding, these engram-bearing (c-Fos) cells are distinguished by
higher mean firing rates (as also seen in a calcium imaging study;
Ghandour et al., 2019), repetitive bursts of action potentials at the
theta frequency, and higher entrainment by the local fast gamma
oscillation compared to the non-c-Fos-expressing place cells,
again highlighting the role inhibitory circuits and oscillations may
play in the formation of the index. Interestingly, when mice were
returned to the context the next day, c-Fos-positive engram neu-
rons, while remaining place cells (meaning they still demonstrated
a reliable in-session spatially receptive field), showed a much
higher degree of spatial instability compared to the encoding ses-
sion (remapping) than the c-Fos-negative place cell population.
These data can be seen as paradoxical; how is it that the neurons
shown to be capable of reinstating context-appropriate behavior
show relatively lower spatial specificity than the remaining active
cells? Importantly, when only firing rate (and not location) was
considered, it was clear that the engram cells faithfully encoded
contextual identity, but not specific location. A return to the en-
coding context resulted in c-Fos-positive neurons reinstating their
ll
average firing rates, which were highly correlated between the first
and second visits, while the firing rates in a distinct context were
strongly altered. It worth noting that this strong correlation of ac-
tivity emerges as soon as animal is placed in the environment,
suggesting their activity could support rapid retrieval of contextual
memory, consistent with the indexing theory. Further, these find-
ings of a unique physiology suggest the importance of the tempo-
ral relationship between input from CA3 and the EC in triggering
CA1 pyramidal cell plasticity and activity in vivo (Bittner et al.,
2017; Ketz et al., 2013).
Complementary results were also found in a physiological study
in which c-Fos-positive CA1 neurons were inhibited during recall
(Trouche et al., 2016). In this study, engram neurons, defined by
c-Fos expression associated with the acquisition of a cocaine-re-
warded CPP, were labeled with an inhibitory opsin. Inactivation of
this ensemble during a subsequent recall session reduced CPP
behavior and, interestingly, led to a global remapping of the
c-Fos-negative active place cell population. Together, these
data suggest that the role of the c-Fos-positive place cells is to
serve as a context-specific memory index and that their activity
is crucial for the stable reinstatement of a more detailed spatial
map, consisting of the remainder of the place cell population,
that would permit animals precise navigation.
While it may seem odd at first that the neurons indispensable
for inducing memory recall in CA1 show spatial instability, recent
computational modeling lends support to this view (Benna and
Fusi, 2019). Based on an assumption that the hippocampus en-
codes correlations of incoming sensory information, similar to
the interpretation from contextual conditioning and IEG studies,
the model predicted instability in the spatial representation of
the hippocampus. Their ultrametric tree-like network generated
sparse and compressed representations of inputs to efficiently
store uncorrelated patterns in a hippocampal-like network.
When spatial navigation in a 2D open field is simulated, activities
of hippocampal cells in the model exhibit strong modulation by
the animal’s location within the environment (i.e., place cells).
However, similar to the experimental observations above, these
place fields significantly remapped between epochs in the
same environment, suggesting instability of firing location as a
reflection of correlation coding rather than spatial coding. Taken
together, these studies support a view that activity of the hippo-
campal engram reflects more than just space and suggest at least
a subset of neurons are dedicated to capturing the conjunctive
correlations that define the larger context of the experience.
Activity-Dependent Regulation of Gene Expression and
Connectivity
Hippocampal engrams are generated and maintained by
strengthening or modification of synapses among activated cells
within and across subregions. One study found that c-Fos-tagged
CA3 cells preferentially responded to stimulation of engram-
tagged DGCs (Ryan et al., 2015), results indicative of experi-
ence-driven connectivity of DG-CA3. Likewise, context-fear-
dependent increases in the number and size of spines in
engram-bearing cells of CA1 coincide with direct input from
engram-tagged cells from CA3 (Choi et al., 2018). Additionally,
DG engram cells were shown to exhibit greater connectivity
with stratum lucidum PV+ INs than non-engram DG cells (Guo
et al., 2018). These observations have motivated investigations
Neuron 107, September 9, 2020 9
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
ll
into how developmental programs and activity-dependent gene
expression prescribe engram formation. First, principal neurons
may have differing propensities toward recruitment into engrams
based on developmentally programmed intrinsic firing properties
and connectivity (Cembrowski and Spruston, 2019; Soltesz and
Losonczy, 2018). Second, activity-dependent transcription fac-
tors and combinations thereof enable neurons to read
patterns of neural activity and transcribe molecular specifiers of
connectivity to facilitate strengthening or modification of synap-
ses (Tyssowski et al., 2018). For example, cyclic adenosine mono-
phosphate (cAMP)-response-element-binding protein (CREB)-
overexpression studies have revealed that enhancing basal
activity and excitability of principal cells in the hippocampus (or
subsets of amygdalar neurons, etc.) prior to learning can bias
the allocation and tagging process to these cells without altering
the overall size of the engram per se (Josselyn and Frankland,
2018; Josselyn and Tonegawa, 2020). A recent report using
RNA sequencing of engram-tagged DG cells (following contextual
fear conditioning) identified a unique learning-dependent genetic
profile for engram-bearing cells, with CREB-dependent transcrip-
tion networks being differentially regulated and required for
consolidation (Rao-Ruiz et al., 2019). Interestingly, many of these
genes were previously shown to regulate somatic inhibition (e.g.,
neuronal PAS domain protein 4 [NPAS4], proenkephalin [Penk],
and brain-derived neurotrophic factor [BDNF]) (Bloodgood
et al., 2013). Consistent with these findings, within the DG,
contextual fear learning regulates CREB-dependent levels of neu-
ropeptide Y (NPY) in SST+ hilar perforant path-associated (HIPP)
interneurons, which may regulate SST+ HIPP-mediated feedback
and feed-forward inhibition in the DG to govern the size of the
engram (Raza et al., 2017; Stefanelli et al., 2016). Not surprisingly,
different IEG transcription factors (including NPAS4) have been
functionally implicated in linking principal cells with distinct IN net-
works to support engram formation (Sun et al., 2020). Thus, expe-
riential input may drive unique IEG expression to govern functional
allocation of engram-bearing cells to work in concert for memory
expression (Figure 4B).
Hippocampal Index Stability and Memory Fidelity
Memory consolidation is thought to involve transformation and
reorganization of hippocampal-linked cognate cortical represen-
tations and a gradual decay of the hippocampal engram over
time (DeNardo et al., 2019; Guskjolen et al., 2018; Kitamura
et al., 2017; Roy et al., 2017; Tayler et al., 2013; Winocur et al.,
2007). Consolidated memories have been shown to generalize
or lack detail, including the extent to which they may elicit
visceral or physiological reactions, leading to the suggestion
that the role the hippocampus plays in memory is to contribute
episodic detail (Yonelinas et al., 2019). If this contribution relies
on the initial memory trace or not remains a contested topic.
For example, it has been argued that hippocampal memory
traces remain, even for older memories (Moscovitch and Nadel,
2019), but others have argued there is a shift in the role the hip-
pocampus from one of recall to reconstruction in the absence of
the original trace, with the activity serving to index consolidated
neocortical traces (Barry and Maguire, 2019a, 2019b). These
observations raise the following questions: Is the hippocampal
index always necessary for memory retrieval, or do cortical in-
10 Neuron 107, September 9, 2020
Perspective
dexes acquire this function over time? Is the cortical index equiv-
alent to the hippocampal index?
Several lines of evidence support the notion that the hippo-
campal index may be necessary for maintenance and retrieval
of only highly precise memories. First, although hippocampal
damage at remote time points may still permit retrieval of
detailed contextual representations, the extent of memory
retrieval is often much less robust (Wang et al., 2009), suggesting
that extrahippocampal indices may not fully compensate for the
loss of the hippocampal index. Indeed, while a similar degree of
hippocampal activation is seen for recent and remote memories,
the reactivation patterns are different (Tayler et al., 2013; see also
Guskjolen et al., 2018). Second, artificially stabilizing the engram
within DG-CA3 decreases remote memory generalization (and
maintains behavioral reinstatement of remote DG engram stimu-
lation; Guo et al., 2018), providing a direct link between mainte-
nance of the hippocampal index and remote memory precision.
However, maintenance of separate hippocampal indices for all
episodic memories is thought to require significantly greater ca-
pacity than is available to avoid memory interference (McClel-
land et al., 1995; Miller and Sahay, 2019; Skaggs and McNaugh-
ton, 1992). In CA1, the various methods employed to genetically
label engram neurons typically capture 20% of the pyramidal
cells in the region (Tanaka et al., 2018), and in vivo imaging sug-
gested that the identity of these allocated neurons shifts over the
timescale of hours (Cai et al., 2016); thus, it appears that natural
decay of hippocampal indices ensures the time-dependent reor-
ganization of memory traces to support different degrees of
generalization and generation of schema to facilitate new
learning. It may be that some hippocampal indexes, perhaps
for salient life events, are maintained for longer periods of time,
thereby permitting recall of remote memories with high fidelity.
The integrity and composition of the cortical indices depends
on how competition for representation of episodic memories and
abstraction of statistical commonalities across ensembles
dictate the balance between preservation of details versus gen-
eration of schema to facilitate memory generalization. This may
involve time-dependent changes in the exact number of cells
and patterns of efferent connectivity of cortical ensembles and
linkage of distinct engrams of separate experiences via some
degree of overlapping and synchronous activation (during recall
or reconsolidation) of engram-bearing cells (Abdou et al., 2018;
DeNardo et al., 2019; Kitamura et al., 2017; Ohkawa et al.,
2015; Oishi et al., 2019; Pignatelli et al., 2019; Ramirez et al.,
2013; Redondo et al., 2014).
While no one model can explain all the current data, from the
perspective of engrams and indexing, we favor the hypothesis
of a time-dependent shift in the indexing function from the hippo-
campus to cortical traces concurrent with a silencing or loss of
the original hippocampal index (Tonegawa et al., 2018). Ulti-
mately, time-dependent shifts in hippocampus-dependent
episodic detail may be useful in the development of experiential
schemas and broader knowledge.
Hippocampal Dysfunction
Indexopathies
Memory deficits and hippocampal dysfunction accompany
traumatic brain injury, epilepsy, age-related cognitive decline,
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
Perspective
Figure 5. Outstanding Challenges for Hippocampal Indexing and Memory Research
Alzheimer’s disease (AD), and numerous other psychiatric disor-
ders, including posttraumatic stress disorder (PTSD) and schizo-
phrenia (Besnard and Sahay, 2016; Haberman et al., 2017; Small
et al., 2011). Can these disorders of experiential memory be clas-
sified as ‘‘indexopathies,’’ insofar as they are marked by an
inability to accurately or precisely encode or effectively
implement hippocampus-dependent routing of information
(i.e., indexing)? For example, recent work documented declining
hippocampal and cortical reinstatement in aging individuals
(Trelle et al., 2020). Disease- or aging-induced excitation-inhibi-
tory imbalance in hippocampal circuits, which may impede in-
dexing, may underlie much of these memory dysfunctions.
Indeed, excitation-inhibition imbalance (hypo- or hyperactivity)
at the level of CA1 (e.g., Oh et al., 2013) and CA3 (e.g., Simkin
et al., 2015; Wilson et al., 2005) and loss of feed-forward inhibi-
tion in DG-CA3 (e.g., Guo et al., 2018) are associated with mem-
ory imprecision in preclinical models of aging and memory disor-
ders. Human imaging studies have further reported similar
activity changes (e.g., hyperactivity) of hippocampal structures
(Haberman et al., 2017), such as in presymptomatic familial AD
(FAD) individuals (Quiroz et al., 2010) or patients with amnestic
mild cognitive impairment (Bakker et al., 2012).
Such cellular, circuit, and network-level alterations may
disrupt the balance between pattern separation and pattern
completion, thereby promoting aberrant index-dependent rein-
statement and recall. What previously may have been subthresh-
old to trigger CA3-dependent memory recall prior to disease may
be sufficient after disease onset, thereby promoting excessive
reinstatement and memory expression in contexts that may
not be optimal. For example, aberrant or excessive retrieval of
past experiences has been suggested to underlie psychosis in
schizophrenia (Tamminga et al., 2010). Additionally, degradation
of flexible routing to extrahippocampal targets, due to connectiv-
ity losses in disease or injury, may also impede the abilities of the
hippocampus to effectively integrate cortical and subcortical in-
formation for proper encoding and retrieval. Perhaps related to
ll
such circuit loss, AD is considered, in part, a disease of memory
retrieval failure (Leal and Yassa, 2018; Roy et al., 2016).
Promoting Indexing: New Directions in Therapy
Recent advances in technology and medicine have led to a num-
ber of new therapeutic avenues for memory disorders—strate-
gies that may be effective, in part, because they promote or
reestablish hippocampal indexing functions. For example,
growing interest has centered on deep-brain and closed-loop
feedback neuroprosthetics for symptom management in individ-
uals when other lines of treatment have failed (Grosenick et al.,
2015; Takeuchi and Berényi, 2020). Perhaps by restoring
context-dependent routing (and thereby indexing), these real-
time electrophysiological (or opto- or chemogenetic, potentially)
methods could dynamically normalize aberrant activity or restore
cell excitability in perturbed brain circuits (e.g., in hippocampal-
amygdalar or hippocampal-prefrontal loops). Additionally,
recent developments in targeted gene-editing approaches
(Knott and Doudna, 2018) may permit molecular reallocation or
respecification of connectivity aimed at promoting memory pre-
cision and accuracy. Indeed, quieting disease-related hyperex-
cited CA3 pyramidal cells may involve targeting feed-forward
inhibitory mechanisms of DG-CA3 (Guo et al., 2018; Viana da
Silva et al., 2019) or CA2-CA3 connections (Boehringer et al.,
2017) or inhibiting aberrant LH-CA3 activity (Zhou et al.,
2019a), for example. Other pharmaco- or gene therapies that
promote neurogenesis in aging or disease states may also exist
as beneficial therapeutic avenues for memory impairments
(Miller and Sahay, 2019).
Novel treatments for memory impairments may not be limited
to invasive techniques and may involve supplementing existing
procedures to best tap into the indexing properties of the hippo-
campus. For example, although the use of mnemonic devices for
memory treatments is not new, recent developments in technol-
ogy, such as augmented reality or 3D interactive environments,
may provide novel avenues for improving memory recall within
and beyond the clinic. Indeed, the growing ubiquity of personal
Neuron 107, September 9, 2020 11
 Please cite this article in press as: Goode et al., An Integrated Index: Engrams, Place Cells, and Hippocampal Memory, Neuron (2020), https://doi.org/
10.1016/j.neuron.2020.07.011
ll
handheld devices may make mobile reminders or mnemonic
cues (to facilitate reinstatement of memory) for treatments or
symptom management for memory impairments more acces-
sible or specialized. When combined with psychological treat-
ments in the clinic, these and the abovementioned possibilities
may yield new successes in treatment-resistant memory disor-
ders. Moving forward, indexing may be a useful framework for
improving clinical therapies for memory dysfunction.
Conclusions: Moving Memory Forward
Perhaps the brain’s most powerful search engine, the hippo-
campus, sits at the center of the acquisition and recall of
episodic memory. While the mechanisms of how this is
achieved have been the focus of decades of research across
many species and disciplines, it is often challenging to relate
disparate lines of inquiry. Here, we have highlighted human
and animal work based on recent genetic, physiological,
anatomical, and computational approaches that together sup-
port an expanded view of the hippocampal memory indexing
theory. In particular, we argue that (1) the functional roles of pu-
tative hippocampal engram cells include indexing, which may
facilitate detailed recall of episodic experiences; (2) this
episodic recall is facilitated by the reinstatement of engram
cell activity and in their experience-sculpted connectivity; (3) in-
dexing may not be unique to the hippocampus, but the hippo-
campus may be uniquely positioned to index experiential mem-
ory; and (4) disease of the hippocampus may impede truly
episodic memory by disrupting its capacity for precise
context-specific reinstatement. Nonetheless, there remain a
number of outstanding questions for the field and for future
work (Figure 5). Future work that integrates these levels of an-
alyses will be required to understand how the dynamics of in-
formation flow in the hippocampal circuit contributes to the en-
coding and recall processes it supports.
ACKNOWLEDGMENTS
T.D.G. acknowledges support from Harvard Brain Science Initiative. K.Z.T. ac-
knowledges support from MEXT Grant-in-Aid for Young Scientists
(19K16305), Grant-in-Aid for JSPS fellows (19J00974), and a Nakajima Foun-
dation research grant. A.S. acknowledges support from NIH Biobehavioral
Research Awards for Innovative New Scientists (BRAINS) 1-R01MH104175,
NIH-NIA 1R01AG048908-01A1, NIH 1R01MH111729-01, the James and Au-
drey Foster MGH Research Scholar Award, the Ellison Medical Foundation
New Scholar in Aging, the Whitehall Foundation, the Inscopix Decode Award,
the NARSAD Independent Investigator Award, Ellison Family Philanthropic
support, the Blue Guitar Fund, a Harvard Neurodiscovery Center/MADRC
Center pilot grant award, an Alzheimer’s Association research grant, the Har-
vard Stem Cell Institute (HSCI) development grant, and an HSCI seed grant.
T.J.M. acknowledges support from MEXT Grant-in-Aid for Scientific Research
(19H05646), MEXT Grant-in-Aid for Scientific Research on Innovative Areas
(17H05591, 17H05986, and 19H05233), and the RIKEN Center for Brain
Science.
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